PPARδ ligand L-165041 ameliorates Western diet-induced hepatic lipid accumulation and inflammation in LDLR-/- mice

Although peroxisome proliferator-activated receptor delta (PPAR delta) has been implicated in energy metabolism and lipid oxidation process, detailed roles of PPAR delta in lipid homeostasis under pathologic conditions still remain controversial. Thus, we investigated the effect of PPAR delta ligand L-165041 on Western diet-induced fatty liver using low-density lipoprotein receptor-deficient (LDLR-/-) mice. LDLR-/- mice received either L-165041 (5 mg/kg/day) or vehicle (0.1 N NaOH) with Western diet for 16 weeks. According to our data, L-165041 drastically reduced lipid accumulation in the liver, decreasing total hepatic cholesterol and triglyceride content compared to the vehicle group. Gene expression analysis demonstrated that L-165041 lowered hepatic expression of PPAR gamma, apolipoprotein B, interleukin 1 beta (IL-1 beta), and interleukin-6. In contrast, L-165041 increased hepatic expressions of PPAR delta, lipoprotein lipase (LPL), and ATP-binding cassette transporter G1 (ABCG1). Our data suggest that L-165041 might be effective in preventing Western diet-induced hepatic steatosis by regulating genes involved in lipid metabolism and the inflammatory response. (C) 2009 Elsevier B.V. All rights reserved.